Abstract We propose the most comprehensive study ever undertaken to delineate roles of pesticides in age-related olfactory impairment (OI), and to examine their relevance to prodromal development of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). About 15-25% of older US adults have various levels of OI, a sensory impairment that most do not even realize they have. Nonetheless, OI independently predicts short-term and long-term mortality, and adversely affects nutrition, safety, and quality of life. OI is also one of the most important early symptoms of AD and PD. Pesticide exposure is ubiquitous and has been linked to a higher risk of PD and potentially to AD, but reliable assessment of pesticide exposure in population-based studies has been a major hurdle to advancing the science in this field. Our multidisciplinary team of epidemiologists, biostatisticians, exposure assessment experts, clinical scientists, and a neurotoxicologist will break new ground in this area by dissecting the connections among pesticides, age-related OI, and neurodegenerative diseases. We will leverage resources from the world's largest collection of human data on acute and chronic pesticide exposure, the Agricultural Health Study (AHS), established in 1993 and still ongoing. Most AHS participants are now aged ?60 years and thus at risk for neurodegenerative diseases. By objectively testing the sense of smell of ~2,700 AHS farmers and conducting in-home clinical assessments for ~600 farmers, we expect to build a large, unique, and lasting resource for the proposed research and beyond. Our Specific Aims are to: 1) delineate the associations of chronic exposure to pesticides with OI among farmers; 2) analyze high pesticide exposure events in relation to OI; and 3) assess whether OI is an important mediator in pesticide-related AD and PD. The Scientific Rigor of this project is assured by the large sample size, state-of- the-science exposure and outcome assessments, carefully planned statistical analyses, and a very experienced multidisciplinary and multi-institutional research team. Innovation: This project will significantly advance our knowledge of long-term neurosensory and neurodegenerative consequences of pesticide exposures by cultivating 20 years of extensive data collection in a well-characterized farming population. Significance: We will bring new insights into the relationship between pesticide exposure and OI, and increase understanding of OI as an early warning marker for AD and PD development in association with pesticide exposure. This project will lay a solid foundation for future longitudinal research with biomarkers (e.g., neuroimaging-based or fluid-based) to conclusively define roles and mechanisms of various pesticides in age-related OI and neurodegeneration.